Sustained release ranolazine formulations

ABSTRACT

A sustained release ranolazine formulation contains an intimate mixture of ranolazine and a partially neutralized pH-dependent binder to form a film that is mostly insoluble in aqueous media below pH 4.5 and soluble in aqueous media above pH 4.5. The formulation is suitable for twice daily administration of ranolazine and is useful for controlling the rate of dissolution of ranolazine, and to maintain human plasma ranolazine levels at between 550 and 7500 ng base/mL.

BACKGROUND OF THE INVENTION

[0001] This application claims priority to U.S. Provisional PatentApplication serial No. 60/099804 filed on Sep. 10, 1998.

[0002] 1. Field of the Invention

[0003] This invention relates to a method for using an orallyadministered sustained release ranolazine dosage formulations tomaintain human ranolazine plasma levels at therapeutic levels.

[0004] 2. Description of the Art

[0005] U.S. Pat. No. 4,567,264, the specification of which isincorporated herein by reference, discloses ranolazine,(±)-N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)-propyl]-1-piperazineacetamide,and its pharmaceutically acceptable salts, and their use in thetreatment of cardiovascular diseases, including arrhythmias, variant andexercise-induced angina, and myocardial infarction.

[0006] U.S. Pat. No. 5,506,229, which is incorporated herein byreference, discloses the use of ranolazine and its pharmaceuticallyacceptable salts and esters for the treatment of tissues experiencing aphysical or chemical insult, including cardioplegia, hypoxic orreperfusion injury to cardiac or skeletal muscle or brain tissue, andfor use in transplants. Conventional oral and parenteral formulationsare disclosed, including controlled release formulations. In particular,Example 7D of U.S. Pat. No. 5,506,229 describes a controlled releaseformulation in capsule form comprising microspheres of ranolazine andmicrocrystalline cellulose coated with release controlling polymers.

[0007] The presently preferred route of administration for ranolazineand its pharmaceutically acceptable salts and esters is oral. A typicaloral dosage form is a compressed tablet, a hard gelatin capsule filledwith a powder mix or granulate, or a soft gelatin capsule (softgel)filled with a solution or suspension. U.S. Pat. No. 5,472,707, thespecification of which is incorporated herein by reference, discloses ahigh-dose oral formulation employing supercooled liquid ranolazine as afill solution for a hard gelatin capsule or softgel.

[0008] As set forth in application Example 3, the initial trials ofranolazine on humans suffering from angina were failures. The trialsused an immediate release of ranolazine formulation at a dose level of120 mg taken three times daily. Based upon the initial experiments, itwas uncertain whether or not ranolazine could be given to humans in anamount and mode that is effective against angina.

[0009] One problem with conventional oral dosage formulations is thatthey are not ideally suited to ranolazine and its pharmaceuticallyacceptable salts, because the solubility of ranolazine is relativelyhigh at the low pH that occurs in the stomach. Furthermore ranolazinealso has a relatively short plasma half-life. The high acid solubilityproperty of ranolazine results in rapid drug absorption and clearance,causing large and undesirable fluctuations in plasma concentration ofranolazine and a short duration of action, thus necessitating frequentoral administration for adequate treatment.

[0010] There is therefore a need for a method for administeringranolazine in an oral dosage form once or twice daily that providestherapeutically effective plasma concentrations of ranolazine for thetreatment of angina in humans.

SUMMARY OF THE INVENTION

[0011] In a first aspect, this invention is a sustained releaseranolazine formulation where the majority of the formulation consists ofactive ranolazine.

[0012] In another aspect, this invention is a method of treating a humanpatient who is suffering from angina or other coronary disorders byadministering a sustained release ranolazine formulation to the patientonce or twice daily.

[0013] In yet another aspect, this invention is a method for treating amammal having a disease state for which the administration of ranolazineis indicated, comprising the once or twice-daily administration ofsustained release ranolazine formulation of this invention in a mannerthat maintains plasma ranolazine close to minimal effective levelswithout peak fluctuations.

[0014] Still another aspect of this invention is a method of maintaininguseful levels of ranolazine in human plasma by administering aranolazine containing dosage form only one or twice daily.

[0015] This invention includes methods for treating a human patientsuffering from a cardiovascular disease selected from arrhythmias,variant and exercise-induced angina, and myocardial infarction. Themethod includes administering a sustained release pharmaceutical dosageform including at least 50% by weight ranolazine in no more than twotablets per dose to the human patient to maintain ranolazine plasmalevels in the human patient of from about 550 to about 7500 ng base/mLfor at least 24 hours wherein the dose is administered at a frequencyselected from once, twice and three times over 24 hours.

[0016] This invention further includes methods for treating a humanpatient suffering from a cardiovascular disease selected fromarrhythmias, variant and exercise-induced angina, and myocardialinfarction. The method includes administering a sustained releasepharmaceutical dosage form including from about 70 to about 80% byweight ranolazine in no more than two tablets per dose to the humanpatient to maintain ranolazine plasma levels in the human patient offrom about 1000 to about 3900 ng base/mL for at least 24 hours whereinthe dose is administered at a frequency selected from one and two timesover 24 hours.

[0017] This invention also includes pharmaceutical dosage formscomprising at least about 50 wt % ranolazine and at least one pHdependent binder that inhibits the release of ranolazine from thesustained release dosage form when the sustained release dosage form issubjected to an aqueous environment having a pH of the stomach and thatpromotes the release of a therapeutic amount of ranolazine in an aqueoussolution having a pH above about 4.5.

DETAILED DESCRIPTION OF THE INVENTION

[0018] “Ranolazine” is the compound(±)-N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)propyl]-1-piperazine-acetamide,or its enantiomers(R)-(+)-N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)-propyl]-1-piperazineacetamide,and(S)-(−)-N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)-propyl]-1-piperazineacetamideand their pharmaceutically acceptable salts, and mixtures thereof.Unless otherwise stated the ranolazine plasma concentrations used in thespecification and examples refers to ranolazine free base.

[0019] “Optional” and “optionally” mean that the subsequently describedevent or circumstance may or may not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not. For example, “optional pharmaceutical excipients”indicates that a formulation so described may or may not includepharmaceutical excipients other than those specifically stated to bepresent, and that the formulation so described includes instances inwhich the optional excipients are present and instances in which theyare not.

[0020] “Treating” and “treatment” refer to any treatment of a disease ina mammal, particularly a human, and include:

[0021] (i) preventing the disease from occurring in a subject which maybe predisposed to the disease but has not yet been diagnosed as havingit;

[0022] (ii) inhibiting the disease, i.e., arresting its development; or

[0023] (iii) relieving the disease, i.e., causing regression of thedisease.

[0024] “Immediate release” (“IR”) refers to formulations or dosage unitsthat rapidly dissolve in vitro and are intended to be completelydissolved and absorbed in the stomach or upper gastrointestinal tract.Conventionally, such formulations release at least 90% of the activeingredient within 30 minutes of administration.

[0025] “Sustained release” (“SR”) refers to formulations or dosage unitsof this invention that are slowly and continuously dissolved andabsorbed in the stomach and gastrointestinal tract over a period ofabout six hours or more. Preferred sustained release formulations arethose exhibiting plasma concentrations of ranolazine suitable for nomore than twice daily administration with two or less tablets per dosingas described below.

[0026] Plasma ranolazine concentration is a mean concentrationdetermined by analyzing the concentration of ranolazine in as few asfive to as many as ten humans who are on the same dosing schedule. It isimportant that the ranolazine concentration is a mean value because ofvariances in ranolazine concentrations in individuals that may be causedby differences in weight, metabolism, or disease states which may causeone person to metabolize ranolazine faster or slower than an averageperson. The plasma ranolazine levels are determined from drawn bloodonto heparin.

[0027] Definitions of other terms used in this application are:

[0028] ANOVA=analysis of variance

[0029] ATP=adenosine triphosphate

[0030] ECG=electrocardiographic

[0031] ETT=exercise treadmill test

[0032] PDH=pyruvate dehydrogenase

[0033] C_(max)=maximum concentration

[0034] C_(trough)=residual concentration at 8 hours post-dose for IRformulations and 12 hours post-dose for SR formulations A-C of Example2.

[0035] tid=three times per day

[0036] bid=twice daily

[0037] C_(x)=concentration at time x

[0038] T_(max)=time to maximum concentration

[0039] AUC_(x)=area under the curve after x hours or time interval

[0040] Percentages given are percentages by weight, unless otherwisestated. This invention involves sustained release ranolazine dosageforms as well as methods for administering sustained release ranolazinedosage forms of this invention to provide for therapeutic plasma levelsof ranolazine.

[0041] The sustained release ranolazine formulations of this inventionare preferably in the form of a compressed tablet comprising an intimatemixture of ranolazine and a partially neutralized pH-dependent binderthat controls the rate of ranolazine dissolution in aqueous media acrossthe range of pH in the stomach (typically approximately 2) and in theintestine (typically approximately about 5.5).

[0042] To provide for a sustained release of ranolazine, one or morepH-dependent binders are chosen to control the dissolution profile ofthe ranolazine formulation so that the formulation releases ranolazineslowly and continuously as the formulation passed through the stomachand gastrointestinal tract. The dissolution control capacity of thepH-dependent binder(s) is particularly important in a sustained releaseranolazine formulation because a sustained release formulation thatcontains sufficient ranolazine for twice daily administration may causeuntoward side effects if the ranolazine is released too rapidly(“dose-dumping”).

[0043] Accordingly, the pH-dependent binders suitable for use in thisinvention are those which inhibit rapid release of drug from a tabletduring its residence in the stomach (where the pH is-below about 4.5),and which promotes the release of a therapeutic amount of ranolazinefrom the dosage form in the lower gastrointestinal tract (where the pHis generally greater than about 4.5). Many materials known in thepharmaceutical art as “enteric” binders and coating agents have thedesired pH dissolution properties. These include phthalic acidderivatives such as the phthalic acid derivatives of vinyl polymers andcopolymers, hydroxyalkylcelluloses, alkylcelluloses, cellulose acetates,hydroxyalkylcellulose acetates, cellulose ethers, alkylcelluloseacetates, and the partial esters thereof, and polymers and copolymers oflower alkyl acrylic acids and lower alkyl acrylates, and the partialesters thereof.

[0044] Preferred pH-dependent binder materials which can be used inconjunction with ranolazine to create a sustained release formulationare methacrylic acid copolymers. Methacrylic acid copolymers arecopolymers of methacrylic acid with neutral acrylate or methacrylateesters such as ethyl acrylate or methyl methacrylate. A most preferredcopolymer is methacrylic acid copolymer, Type C, USP (which is acopolymer of methacrylic acid and ethyl acrylate having between 46.0%and 50.6% methacrylic acid units). Such a copolymer is commerciallyavailable, from Röhm Pharma as Eudragit® L 100-55 (as a powder) orL30D-55 (as a 30% dispersion in water). Other pH-dependent bindermaterials which may be used alone or in combination in a sustainedrelease ranolazine dosage form include hydroxypropyl cellulosephthalate, hydroxypropyl methylcellulose phthalate, cellulose acetatephthalate, polyvinylacetate phthalate, polyvinylpyrrolidone phthalate,and the like. One or more pH-dependent binders are present in theranolazine dosage forms of this invention in an amount ranging fromabout 1 to about 20 wt %, more preferably from about 5 to about 12 wt %and most preferably about 10 wt %.

[0045] One or more pH-independent binders may be in used in sustainedrelease ranolazine oral dosage forms. It is to be noted thatpH-dependent binders and viscosity enhancing agents such ashydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose,polyvinylpyrrolidone, neutral poly(meth)acrylate esters, and the like,do not themselves provide the required dissolution control provided bythe identified pH-dependent binders. The pH-independent binders arepresent in the formulation of this invention in an amount ranging fromabout 1 to about 10 wt %, and preferably in amount ranging from about 1to about 3 wt % and most preferably about 2.0 wt %.

[0046] As shown in Table 1, ranolazine is relatively insoluble inaqueous solutions having a pH above about 6.5, while the solubilitybegins to increase dramatically below about pH 6. TABLE 1 Solution pHSolubility (mg/mL) USP Solubility Class  4.81 161 Freely soluble  4.8973.8 Soluble  4.90 76.4 Soluble  5.04 49.4 Soluble  5.35 16.7 Sparinglysoluble  5.82 5.48 Slightly soluble  6.46 1.63 Slightly soluble  6.730.83 Very slightly soluble  7.08 0.39 Very slightly soluble  7.59(unbuffered water) 0.24 Very slightly soluble  7.73 0.17 Very slightlysoluble 12.66 0.18 Very slightly soluble

[0047] Increasing the pH-dependent binder content in the formulationdecreases the release rate of ranolazine from the formulation at pH isbelow 4.5 typical of the pH found in the stomach. The enteric coatingformed by the binder is less soluble and increases the relative releaserate above pH 4.5, where the solubility of ranolazine is lower. A properselection of the pH-dependent binder allows for a quicker release rateof ranolazine from the formulation above pH 4.5, while greatly affectingthe release rate at low pH. Partial neutralization of the binderfacilitates the conversion of the binder into a latex like film whichforms around the individual ranolazine granules. Accordingly, the typeand the quantity of the pH-dependent binder and amount of the partialneutralization composition are chosen to closely control the rate ofdissolution of the ranolazine from the formulation.

[0048] The dosage forms of this invention should have a quantity ofpH-dependent binders sufficient to produce a sustained releaseformulation from which the release rate of ranolazine is controlled suchthat at low pHs (below about 4.5) the rate of dissolution issignificantly slowed. In the case of methacrylic acid copolymer, type C,USP (Eudragit® L 100-55), a suitable quantity of pH-dependent binder isbetween 5% and 15%. The pH dependent binder will typically have fromabout 1 to about 20% of the binder methacrylic acid carboxyl groupsneutralized. However, it is preferred that the degree of neutralizationranges from about 3 to 6%.

[0049] The sustained release formulation may also contain pharmaceuticalexcipients intimately admixed with the ranolazine and the pH-dependentbinder. Pharmaceutically acceptable excipients may include, for example,pH-independent binders or film-forming agents such as hydroxypropylmethylcellulose, hydroxypropyl cellulose, methylcellulose,polyvinylpyrrolidone, neutral poly(meth)acrylate esters (e.g. the methylmethacrylate/ethyl acrylate copolymers sold under the trademarkEudragit® NE by Röhm Pharmal, starch, gelatin, sugars,carboxymethylcellulose, and the like. Other useful pharmaceuticalexcipients include diluents such as lactose, mannitol, dry starch,microcrystalline cellulose and the like; surface active agents such aspolyoxyethylene sorbitan esters, sorbitan esters and the like; andcoloring agents and flavoring agents. Lubricants (such as talc andmagnesium stearate) and other tableting aids are also optionallypresent.

[0050] The sustained release ranolazine formulations of this inventionhave a ranolazine content of above about 50% by weight to about 95% ormore by weight, more preferably between about 70%, to about 90% byweight and most preferably from about 70 to about 80% by weight; apH-dependent binder content of between 5% and 40%, preferably between 5%and 25%, and more preferably between 5% and 15%; with the remainder ofthe dosage form comprising pH-independent binders, fillers, and otheroptional excipients.

[0051] Particularly preferred sustained release ranolazine formulationsof this invention consist, essentially of: Weight Preferred MostIngredient Range (%) Range (%) Preferred (%) Ranolazine 50-95 70-90 75Microcrystalline cellulose (filler)  1-35  5-15 10.6 Methacrylic acidcopolymer  1-35   5-12.5 10.0 Sodium hydroxide 0.1-1.0 0.2-0.6 0.4Hydroxypropyl methylcellulose 0.5-5.0 1-3 2.0 Magnesium stearate 0.5-5.01-3 2.0

[0052] The sustained release ranolazine formulations of this inventionare prepared as follows: ranolazine and pH-dependent binder and anyoptional excipients are intimately mixed (dry-blended). The dry-blendedmixture is then granulated in the presence of an aqueous solution of astrong base which is sprayed into the blended powder. The granulate isdried, screened, mixed with optional lubricants (such as talc ormagnesium stearate), and compressed into tablets. Preferred aqueoussolutions of strong bases are solutions of alkali metal hydroxides, suchas sodium or potassium hydroxide, preferably sodium hydroxide, in water(optionally containing up to 25% of water-miscible solvents such aslower alcohols).

[0053] The resulting ranolazine containing tablets may be coated with anoptional film-forming agent, for identification, taste-masking purposesand to improve ease of swallowing. The film forming agent will typicallybe present in an amount ranging from between 2% and 4% of the tabletweight. Suitable film-forming agents are well-known to the art andinclude hydroxypropyl methylcellulose, cationic methacrylate copolymers(dimethylaminoethyl methacrylate/methyl-butyl methacrylatecopolymers-Eudragit® E-Röhm Pharma), and the like. These film-formingagents may optionally contain colorants, plasticizers, and othersupplemental ingredients.

[0054] The compressed tablets preferably have a hardness sufficient towithstand 8 Kp compression. The tablet size will depend primarily uponthe amount of ranolazine in the tablet. The tablets will include from300 to 1100 mg of ranolazine free base. Preferably, the tablets willinclude amounts of ranolazine free base ranging from 400-600 mg, 650-850mg, and 900-1100 mg.

[0055] In order to influence the dissolution rate, the time during whichthe ranolazine containing powder is wet mixed is controlled. Preferablythe total powder mix time, i.e. the time during which the powder isexposed to sodium hydroxide solution, will range from 1 to 10 minutesand preferably from 2 to 5 minutes. Following granulation, the particlesare removed from the granulator and placed in a fluid bed dryer fordrying at about 60° C.

[0056] Surprisingly, it has been found that these methods producesustained release ranolazine formulations that provide lower peak plasmaranolazine levels and yet effective plasma concentrations of ranolazinefor up to 12 hours and more after administration, when the ranolazineused as its free base, rather than as the more pharmaceutically commonranolazine dihydrochloride salt or as another salt or ester. The use ofranolazine free base affords at least one advantage: The proportion ofranolazine in the tablet can be increased, since the molecular weight ofranolazine free base is only 85% that of ranolazine dihydrochloride. Inthis manner, delivery of an effective amount of ranolazine is achievedwhile limiting the physical size of the dosage unit.

[0057] Another advantage of sustained release ranolazine formulations ofthis invention is that they are prepared by a process that essentiallyinvolves only water as a solvent, and utilizes standard pharmaceuticalprocessing techniques and equipment.

[0058] The sustained release ranolazine formulations of this inventioncan be used for treating cardiovascular diseases, including arrhythmias,variant and exercise-induced angina, and myocardial infarction;treatment of tissues experiencing a physical or chemical insult,including cardioplegia, hypoxic or reperfusion injury to cardiac orskeletal muscle or brain tissue, and ischemia; and peripheral arterialdiseases, such as intermittent claudication. It is most preferred thatthe sustained release dosage formulation be used as a mammaliananti-anginal agent and most preferably as a human anti-anginal agent.

[0059] The oral sustained release ranolazine dosage formulations of thisinvention are administered one, twice; or three times in a 24 hourperiod in order to maintain a plasma ranolazine level above thethreshold therapeutic level and below the maximally tolerated levels, ofbetween about 550 and 7500 ng base/mL in a patient. This corresponds toan amount of ranolazine 2 HCl ranging from about 644 ng/mL to about 8782ng/mL. Furthermore, the timing of the oral ingestion of the ranolazineoral dosage forms should be controlled to insure that the plasmaranolazine level does not exceed about 7500 ng base/mL and preferably sothat the plasma ranolazine level does not exceed about 5000 ng base/mLan most preferably so that is does not exceed 3800 ng base/mL. In someinstances it may be beneficial to limit the peak plasma ranolazine levelto no more than about ng base/mL At the same time, the plasma troughranolazine levels should preferably not fall below about 1000 ngbase/mL, and in some instances should not fall below 1700 ng base/mL

[0060] In order to achieve the preferred plasma ranolazine level of fromabout 1000 to about 3800 ng base/mL, it is preferred that the oralranolazine dosage forms described herein are administered once or twicedaily. If the dosage forms are administered twice daily, then it ispreferred that the oral ranolazine dosage forms are administered atabout twelve hour intervals.

[0061] In addition to formulating and administering oral sustainedrelease dosage forms of this invention in a manner that controls theplasma ranolazine levels, it is also important to minimize thedifference between peak and trough plasma ranolazine levels. The peakplasma ranolazine levels are typically achieved at from about 30 minutesto eight hours or more after initially ingesting the dosage form whiletrough plasma ranolazine levels are achieve at about the time ofingestion of the next scheduled dosage form. It is preferred that thesustained release dosage forms of this invention are administered in amanner that allows for a peak ranolazine level no more than 8 timesgreater than the trough ranolazine level, preferably no more than 4times greater than the trough ranolazine and most preferably no greaterthan 2 times trough ranolazine level.

[0062] The sustained release ranolazine formulations of this inventionprovide the therapeutic advantage of minimizing variations in ranolazineplasma concentration while permitting, at most, twice-dailyadministration. The formulation may be administered alone, or (at leastinitially) in combination with an immediate release formulation if rapidachievement of a therapeutically effective plasma concentration ofranolazine is desired or by soluble IV formulations and oral dosageforms.

[0063] The following Examples are representative of the invention, butare not to be construed as limiting the scope of the claims.

EXAMPLES

[0064] These Examples detail methods for manufacturing ranolazine dosageforms as well as experiments performed to evaluate the effectiveness ofranolazine administration and effectiveness. Throughout these Examplesit should be noted that:

[0065] (1) Oral doses of the instant release (IR) formulation were givenas capsules or tablets of the dihydrochloride salt and are expressed asthe dihydrochloride salt.

[0066] (2) Oral doses of the sustained release (SR) formulation weregiven as tablets of the ranolazine base and are expressed as the base.

[0067] (3) When IR and SR formulations were compared in the same study,doses are expressed in terms of both base and dihydrochloride. Theconversion factor for dihydrochloride to base is 0.854 (e.g.: 400 mgdihydrochloride×0.854=342 mg free base equivalent).

[0068] (4) All plasma levels and pharmacokinetic parameters areexpressed as levels of free base.

Example 1

[0069] This Example describes a method of preparing immediate release(IR) ranolazine formulations. Ranolazine dihydrochloride (4000 g),microcrystalline cellulose (650 g), polyvinylpyrrolidone (100 g), andcroscarmellose sodium (100 g) powders were intimately mixed together ina Fielder PMA 65 mixer-granulator, and sufficient water was then added,with mixing to form a granulate. The granulate was dried in an AeromaticStrea-5 fluid bed drier, screened, and mixed with magnesium stearate(100 g). The mixture was filled into hard gelatin capsules to a fillweight of, for example, 500 mg per capsule to achieve a dose of 400 mgof ranolazine dihydrochloride (equivalent to 342 mg of ranolazine freebase) per capsule, but may be filled to fill weight of 30 to 400 mg ofranolazine dihydrochloride.

Example 2

[0070] This Example describes a method of preparing sustained release(SR) ranolazine formulations.

[0071] A sustained release (SR) formulation, designated as SRFormulation A, and including pH-dependent and pH-independent binders wasprepared by combining Ranolazine (2500 g), methacrylic acid copolymer,Type C (Eudragit® L 100-55-Röhm Pharma) (1000 g), microcrystallinecellulose (Avicel®) (100 g) (710 g), and polyvinyl pyrrolidinone powderswere intimately mixed together in a Fielder PMA 65 mixer-granulator. Themixture was granulated with a solution of sodium hydroxide (40 g) inwater, and a 30% aqueous dispersion of methyl methacrylate/ethylacrylate copolymer (Eudragit® NE 30 D-Röhm Pharma) (1667 g) was added tothe wet mass. The resulting granulate was dried in an Aeromatic Strea-5fluid bed drier, screened, and then mixed with croscarmellose sodium(100 g) and magnesium stearate (50 g). The mixture was compressed into684 mg tablets with a Manesty B tablet press to achieve dose of 342 mgof ranolazine free base per tablet. This formulation is referred to asSR Formulation A.

[0072] SR Formulation B was prepared in the same manner as SRFormulation A except that the Eudragit® L 100-55 was reduced to 500 g,and the Eudragit® NE 30 D was replaced by a 40% aqueous dispersion of amethyl methacrylate/ethyl acrylate copolymer (Eudragit® NE 40 D-RöhmPharma) (2500 g). The resulting (SR) formulation included 342 mgranolazine free base per tablet.

[0073] In SR Formulation C, ranolazine free base (342 mgs) was blendedwith microcrystalline cellulose and polyvinyl pyrrolininone K25,granulated with water, dried, and blended with croscarmellose sodium andmagnesium stearate. The blend was compressed into tablets and coatedwith an enteric coating.

[0074] SR Formulation D, including only a pH dependent binder wasprepared by combining Ranolazine (7500 g), Eudragit® L 100-55 (1000 g),hydroxypropyl methylcellulose (Methocel® E5- source) (200 g), andmicrocrysalline cellulose (Avicel®) (1060 g) by intimate mixing. Themixed powders were granulated with a solution of sodium hydroxide (40 g)in water (1900 to 2500 grains). The granulate was dried and screened,mixed with magnesium stearate (200 g), and compressed for example intotablets weighing 667 mg to achieve a dose of 500 mg of ranolazine freebase per tablet. The tablets were spray, coated in a 24 inch Accelacota®cylindrical pan coater with OPADRY film coating solution to a 2-4%weight gain. OPADRY film coating solutions are available in a variety ofcolors from Colorcon, West Point, Pa.

[0075] The stepwise procedure for preparing SR Formulation D is asfollows:

[0076] a) Blend together ranolazine, microcrystalline cellulose,methacrylate copolymer (Type C) and hydroxypropyl methyl cellulose usingan appropriate blender.

[0077] b) Dissolve sodium hydroxide in purified water.

[0078] c) Using appropriate granulation equipment, slowly add the sodiumhydroxide solution to the blend with constant mixing. Add a furtheraliquot of water, if necessary.

[0079] d) Continue mixing to achieve additional massing. Add a furtheraliquot of water, if necessary.

[0080] e) Dry granulated in a fluid bed dryer.

[0081] f) Screen dried granules through an appropriate mill.

[0082] g) Add magnesium stearate to the screened granules and blendtogether.

[0083] h) Pass the granulated material through a chilsonator, if needed.

[0084] i) Compress the granules into tablets using appropriately sizedtooling.

[0085] j) Disperse OPADRY powder in water and film-coat usingappropriately sized coating equipment to a typical level of 2-4% byweight.

[0086] k) Polish with camauba wax using a typical level of 0.002-0.003%by weight.

Example 3

[0087] This Example summarizes a study published in Circulation90:726-734 (1994) that demonstrated that ranolazine was ineffective asan antianginal and anti-ischemic agent when administered as an IRformulation of Example 1.

[0088] Patients with stable angina pectoris took part in the study. Anyprevious antianginal drugs used by the patients were discontinued undermedical supervision. Three hundred nineteen patients receivedsingle-blind placebo for up to 18 days, and 318 stopped exercise becauseof angina of moderate severity, had evidence of myocardial ischemia(≧1-mm ST segment depression), and were randomized to one of four studygroups and administered; ranolazine.2HCl 30 mg tid (n=81);ranolazine.2HCl 60 mg tid (n=81); ranolazine.2HCl 120 mg tid (n=78); andplacebo tid (n=79). After administration of 30-, 60- and 120-mg dosestid, the mean peak plasma concentrations of ranolazine free base at 1hour after dose were 94, 219 and 510 ng/mL, respectively, and the meantrough plasma concentrations at 8 hours after dose were 18, 37 and 90ng/mL, respectively.

[0089] After the 4-week double-blind phase, symptom-limited exercisetests were repeated at 1 hour (peak test) and 8 hours (trough test)after the study medication was administered. Total exercise duration atbaseline (±SEM) was 5.9±0.2 minutes for the placebo group and 6.4±0.3,5.9±0.3, and 6.6±0.2 minutes for the ranolazine 30-, 60-, and 120-mggroups, respectively (P=NS). After 4 weeks of double-blind therapy,compared with baseline values, at 1 hour after the study medication wasadministered (peak effect), total exercise duration (±SEM) increased by0.45±0.2 minutes in the placebo group and by 0.3±0.2, 0.6±0.2, and0.5±0.2 minutes in the ranolazine 30-, 60- and 120-mg groups,respectively (placebo versus ranolazine, P=NS). Times to 1-mm ST-segmentdepression at baseline were similar in the four groups and, after 4weeks of therapy in each group, increased significantly by similarmagnitudes at 1 hour after the administration of the medications.Similar changes were seen for the time to onset of angina. Eight hoursafter administration (trough effect), no differences in total exercisetime or any other exercise variables were observed between the placeboand the ranolazine groups. Compared with the baseline values, the numberof anginal attacks per week and the number and duration of ischemicepisodes per 48 hours during Holter monitoring decreased significantlyby similar magnitudes in the placebo and ranolazine groups.

[0090] These results indicated that therapy with ranolazine.2HCl 30, 60and 120 mg tid was not superior to placebo. The study also did not showbeneficial effects of similar doses of ranolazine on either mycocardialischema or exercise performance or on anginal attacks during daily lifein patients with angina pectoris.

Example 4

[0091] In this Example, the safety and anti-ischemic effects of highplasma ranolazine levels in a large group of angina patients wasevaluated and the duration of any effects during steady-state dosingwith bid and tid regimens was assessed. In this Example, patients withchronic stable angina pectoris who were responsive to conventionalantianginal drugs were treated with 3 ranolazine.2HCl dosing regimens:267 mg tid, 400 mg bid and 400 mg tid IR Formulations of Example 1.Exercise testing parameters and ranolazine free base concentrations weredetermined at peak and trough plasma levels.

[0092] Methods

[0093] The study involved double-blind, placebo-controlled randomizedtreatment phase with 4 treatments (placebo, ranolazine.2HCl 400 mg bid,ranolazine.2HCl 267 mg tid, and ranolazine.2HCl 400 mg tid), 4 treatmentsequences and 5 double-blind treatment periods in an extended periodLatin square design on pre-qualified patients who were responsive toknown antianginal therapy and had stable exercise times.

[0094] Human patients with chronic stable angina pectoris, of at least 3months' duration, that had responded to conventional antianginal therapywere considered candidates. In addition, patients had to haveelectrocardiogrpahic (ECG) evidence of exercise-induced ischemia basedupon horizontal or down-sloping ST-segment depression of ≧1 mm thatpersisted in 3 consecutive beats during an exercise stress test and anECG pattern that would not interfere with interpretation of ST-segmentchanges. The latter criterion specifically excluded patients with leftventricular hypertrophy, pre-excitation, conduction abnormalities, orpacemaker rhythm. Other exclusion criteria included unstable angina ormyocardial infarction within the preceding 3 months, heart failuredefined as New York Heart Association Class III or IV, significantvalvular or congenital heart disease that was uncorrected, need fordigoxin or long-acting nitrate therapy, labile diabetes mellitus, orother serious conditions that would confuse follow-up evaluation.

[0095] These immediate release ranolazine.2HCl dosing regimens (267 mgtid, 400 mg bid, 400 mg tid) and a placebo were administered during thetreatment phase. Patients took one capsule containing either 267 mg or400 mg of ranolazine dihydrochloride, or placebo at 8:00 a.m., 4:00p.m., 8:00 p.m. and 12:00 a.m. All capsules were identical inappearance. Patients were randomized to 1 of 4 treatment sequences, with25% of the patients assigned to each sequence. Each treatment wasadministered for 1 week, with one treatment repeated during a fifth1-week period.

[0096] To qualify patients receiving their usual antianginal medicationsunderwent a screening exercise treadmill test (ETT-1) using a Sheffieldmodified Bruce protocol. If the time to onset angina was ≧3 but ≦13minutes, an antianginal drug was withdrawn and treatment withsingle-blind placebo was initiated. After 1 to 2 weeks, patientsreturned for another ETT (ETT-2). If the time to onset angina decreasedby 1 minute compared with ETT-1, the patient was considered to havecompleted the first qualifying ETT. If the decrease in time to onsetangina was not ≧1 minute, a second antianginal drug could be withdrawnand the above sequence repeated. If necessary, a third antianginal drugcould be withdrawn according to this procedure in order for the patientto qualify. Long-acting nitrates were always withdrawn first;beta-blockers; and calcium antagonists could be withdrawn in eitherorder from patients not receiving long-acting nitrates. After thepatient achieved the first qualifying ETT (ETT-2), a second qualifyingETT (ETT-3) was performed in which the time to onset angina had to bewithin ±15% of that observed during ETT-2. In addition, each of thequalifying ETTs had to have ECG signs of ischemia (≧1 mm horizontal ordown-sloping ST-segment depression in 3 consecutive beats). Patientsmeeting these criteria were used in the study.

[0097] After each 1 week period, patients returned to the exerciselaboratory in the morning, at least 1 hour after a light breakfast, foran ETT. This was designated the trough ETT; the trough ETTs wereperformed at the same time of day for each patient. After completing thetrough ETT, the patient, received the next scheduled blinded medicationdose from the blister pack used that week. Another ETT was performed 1hour after the administered dose. This was designated the peak ETT.Blood samples were obtained at trough (approximately 8 hours afterdosing) and at peak (1 hour after dosing). Other standard laboratorytests were monitored regularly throughout the study.

[0098] Blood pressure (by cuff) and heart rate were monitored before allETTs, during the ETT, during the last minute of each stage of the test,at onset angina, at the point of maximum exercise, and during recovery(every minute for 4 minutes, then every 5 minutes until values returnedto baseline). Heart rates also was monitored continuously and standard12-lead ECG recordings were done immediately before exercise with thepatient standing on the treadmill, at the end of each stage of exercise,at the maximally tolerated exercise load, and at the termination ofexercise.

[0099] Mean treadmill exercise times for the 3 exercise variables ofinterest during placebo and the different ranolazine dosing regimens(ranolazine-placebo) for all patients at peak and trough are summarizedin Table 2 below. TABLE 2 Exercise Test Data for All Patients at Peakand Trough Treatment Mean Excercise Variable (all Double- Ranola-patients, blind zine 400 Ranolazine Ranolazine minutes) Placebo mg bid267 mg tid 400 mg tid Time to Peak 9.01 9.33 9.40 9.33 onset anginaTrough 8.58 8.77 8.78 8.65 Exercise Peak 10.67 10.83 10.87 10.84Duration Trough 10.50 10.55 10.56 10.60 Time to 1 Peak 9.58 9.86 9.999.94 mm ST Trough 9.04 9.22 9.22 9.31 depression

[0100] At peak ranolazine plasma concentrations, all ETT ischemiaparameters were prolonged over placebo and most notably, the time toonset of 1-mm ST-segment depression. In the all-patients analysis, theincrease in time to onset angina over placebo ranged from 0.32 to 0.39minutes (p≦0.01) and time to onset of 1-mm ST-segment depression rangedfrom 0.28 to 0.41 minutes (p≦0.02) for each of the 3 ranolazine dosingregimens and all regimens combined. Also, the total duration of exercisewas significantly increased for all regimens combined and trends ofsimilar direction and magnitude were noted for each dosing regimen. Inthe per-protocol analysis each of the 3 ETT parameters were prolonged(p≦0.01) for all ranolazine dosing regimens combined. All individualranolazine dosing regimens significantly prolonged time to 1-mmST-segment depression and nonsignificant trends of similar direction andproportions were found for time to onset angina and duration ofexercise. In general, results of the per-protocol analysis, except thatthe magnitude of the effect appeared to somewhat greater in those withmonotherapy.

[0101] At trough plasma concentrations, ranolazine had a lesser effecton ETT parameters. The results for the all-patients and per-protocolanalyses were relatively consistent, demonstrating trends to increasedexercise times. But only the time to 1 mm ST-segment depression for allranolazine regimens combined in the all-patients analysis achievedstatistical significance.

[0102] In view of the more pronounced increases in exercise parametersobserved with ranolazine monotherapy, the responses to ranolazine amongpatients receiving different concomitant antianginal medications wereanalyzed. These post-hoc analyses were performed on peak ranolazinedata, when the effects to improve exercise times were most evident.Because long-acting nitrates were withdrawn first during thesingle-billed qualifying phase, no patient entered double-blindtreatment receiving long-acting nitrates. Of patients with peak efficacydata, 34% (107/312) of the patients received beta-blockers duringdouble-blind treatment and 24% (75/312) received calcium antagonists.

[0103] Exercise test parameters improved at peak ranolazineconcentrations (ranolazine-placebo) whether or not patients werereceiving beta-blockers. These improvements were slightly larger inmagnitude in the 205 patients not receiving beta-blockers compared tothe 107 patients who received beta-blockers. But the differences betweenthose receiving beta-blockers and those not receiving them did notachieve statistical significance for any exercise parameter. In patientsnot receiving beta-blockers, all exercise parameters improvedsignificantly on each of the 3 ranolazine regimens, and also with allranolazine regimens combined. Similar trends were observed in thesmaller number of patients receiving beta-blockers. Analyses of exercisedata from patients taking calcium antagonists compared with those notreceiving calcium antagonists produced similar findings.

[0104] Table 3 below summarizes the mean peak and trough plasmaranolazine concentrations, in terms of ranolazine dihydrochloride base,for all patients by gender and for each dosing regimen. TABLE 3 Mean (±Standard Deviation) Ranolazine Plasma Concentrations by Dosing RegimenRanolazine 400 Ranolazine 267 Ranolazine 400 mg mg bid mg tid tid Peak(ng/mL) All Patients 1882 (1094) 1346 (823) 2128 (1198) Males 1762(999)  1261 (774) 1917 (1046) Females 2171 (1253) 1594 (904) 2654 (1385)Trough (ng/mL) All Patients 235 (288)  316 (336) 514 (500) Males 235(264)  316 (336) 518 (494) Females 235 (342)  316 (340) 505 (517)

[0105] The plasma mean peak concentrations ranged from 1346 to 2128 ngper mL ranolazine free base. The 400 mg tid dosing regimen wasassociated with the highest ranolazine plasma concentrations. Meantrough ranolazine plasma concentrations ranged from 235 to 514 ng permL. Mean peak ranolazine plasma concentrations were somewhat higher infemales than in males, but there were no sex differences in plasmaconcentrations evident in trough.

[0106] At peak ranolazine plasma concentrations, there were nostatistically significant differences among any of the ranolazine dosingregimens and placebo for double product. Likewise, at trough ranolazineplasma concentrations, there were no statistically significantdifferences among the 3 ranolazine dosing regimens and placebo in theper-protocol analysis for standing or maximum exercise double product.

[0107] The results of this study suggest that ranolazine is an effectiveantianginal and anti-ischemic compound in patients with chronic stableangina pectoris. At peak plasma concentrations, the three ranolazinedosing regimens used prolonged time to onset of angina and duration ofexercise as well as time to 1-mm ST-segment depression on average about0.33 minutes over that observed with placebo. Improvement in exerciseparameters was observed in the present study not only in patientsreceiving concomitant antianginal therapy (eg, beta-blockers and calciumantagonists), but also in the subgroup who received only ranolazinemonotherapy. In the latter patients, the treatment effect appeared to besomewhat greater in magnitude. This suggests that ranolazine also may beuseful in monotherapy in patients with chronic stable angina pectoris.

[0108] The hemodynamic findings indicate that the improvement inexercise parameters in peak ranolazine plasma concentrations was notassociated with changes in blood pressure or heart rate. Thenonhemodynamic mechanism of action of ranolazine, therefore, differsfrom that of other antianginal drugs in current clinical use.

[0109] Most important, we documented that the antianginal andanti-ischemic effects of the immediate-release ranolazine preparationstudied did not persist throughout the dosing interval. Although time toonset of ischemic-type ST-segment depression was significantly prolongedand trends of similar direction were noted for other ETT parameters, theeffect was minimal at trough ranolazine plasma concentrations. Mean peakranolazine free base plasma concentrations ranged from 1346 to 2128 ngper mL, while mean trough plasma concentrations ranged from 235 to 514ng per mL. It seems evident that the higher mean ranolazine plasmaconcentrations observed at peak are associated with clinicallymeaningful antianginal and anti-ischemic effects, whereas concentrationsobtained at trough were not.

[0110] Based on the results of the present experiment, the thresholdplasma ranolazine free base concentration for anti-ischemic activitydetected during ETT is likely to lie above about 550 ng per mL. Further,it is likely that ranolazine plasma concentrations must be maintained ator above the threshold value throughout the dosing interval to ensureantianginal and anti-ischemic activity during exercise throughout thisinterval.

[0111] Ranolazine was well tolerated over the plasma concentrationsachieved in the present study. The rate of occurrence of adverse eventsdid not differ among the ranolazine dosing regimens and placebo, andthere were no drug-related changes in ECG intervals or complexmorphology. In addition, there were no clinically significant changes inblood glucose concentrations, lipid values or liver function tests,suggesting that the metabolic effect of ranolazine does not extend tosystemic glucose regulation or lipid metabolism.

[0112] Ranolazine improves exercise parameters with no detectable effecton heart rate and blood pressure in patients with chronic stable anginapectoris. It is likely that a threshold ranolazine plasma concentrationabove about 550 ng per mL must be obtained to detect these antianginaland anti-ischemic effects. Ranolazine is well tolerated over a widerange of plasma concentrations. Further study using larger doses of asustained release preparation are warranted to fully evaluate this novelmetabolic concept for management of ischemia.

Example 5

[0113] I. In vitro Comparison of IR Formulation and SR Formulations

[0114] The IR Formulation prepared according to Example 1 and the SRFormulations prepared according to Examples 2A-2C were tested in a USPApparatus 2 dissolution tester, using 900 mL of 0.1M hydrochloric acidas the dissolution fluid to simulate dissolution in the stomach. TABLE 4Percentage of Formulation Dissolved Time Formulation (hours) IR A B C0.25 88.1 0.5 100.5 13.9 17.6 17.5 1 101.7 19.9 26.0 25.7 2 27.8 47.535.9 4 39.0 69.2 48.4 8 52.4 90.1 64.7 12 61.6 99.6 74.2 24 80.8 105.695.4

[0115] The tabular results show that while the IR Formulation iscompletely dissolved in no more than 0.5 hours (as expected for animmediate release formulation), SR Formulations A, B, and C displayed aprolonged dissolution of a low pH, as is desirable for a sustainedrelease formulation.

[0116] II. In vivo Comparison of IR Formulation and SR Formulations A,B, and C

[0117] Single doses of the IR Formulation prepared according to Example1 and SR Formulations A and B prepared according to Example 2 wereadministered to eleven healthy volunteers and their plasmaconcentrations of ranolazine free base were measured at 0, 20, 40, 60,90, and 120 minutes, hourly to six hours, twice-hourly to eighteenhours, and at twenty-four hours after administration (SR Formulationsonly). The results are set forth in Table 5 below. TABLE 5 FormulationIR A B C C_(max) (ISD) 1940 (807) 753 (264) 657 (316) 925 (747) (ng/mL)C_(trough) (ISD) 165 (111) 158 (114) 182 (110) 290 (163) (ng/mL) T_(max)(ISD) 1.27 (0.5) 4.09 (1.14) 4.05 (1.31) 6.55 (2.93) (hours) AUC₀₋₂₄(ISD) 6530     5640     5280     5820     (ng. hr/mL)

[0118] From Table 5 it is apparent that SR Formulations A, B and C ofthis invention exhibit dissolution properties which make them suitablefor twice daily administration of ranolazine.

Example 6

[0119] This Example details a single-ascending dose, crossover-designstudy that assessed the safety and pharmacokinetic profile of singleoral dose of ranolazine base SR Formulation of Example 2D. Humansubjects were divided into three groups. Group 1 received 500, 750 and1000 mg ranolazine SR. Group 2 received 1250 and 1750 mg ranolazine SR.Group 3 received 1500 and 2000 mg ranolazine SR. Each group also had arandomized placebo phase. Mean pharmacokinetic parameters followingsingle oral doses of the ranolazine SR does are detailed in Table 6below: TABLE 6 Mean ± SD Pharmacokinetic Parameters (n = 8 except* n =7) Dose SR C_(max) AUC_(0-30 rh) (mg) Group (ng/mL) C_(trough) (ng/mL)T_(max) (hr) (ng. hr/mL) 500 1 883 ± 353 382 ± 251 4.63 ± 1.19 9380 ±4250 750 1 1300 ± 1060 455 ± 353  4.25 ± 0.886 12500 ± 9000  1000 1*1610 ± 959  695 ± 438 5.71 ± 2.14 18100 ± 9630  1250 2 2210 ± 716  943 ±541 6.21 ± 3.52 25000 ± 8090  1500 3 1980 ± 1050 1070 ± 754   4.75 ±0.886 25400 ± 16000 1750 2 3670 ± 1570 2400 ± 1260 5.25 ± 2.31 49200 ±18200 2000 3 2440 ± 1120 1640 ± 937  5.21 ± 2.30 35400 ± 19100

[0120] The pharmacokinetic results reported in Table 6 indicate thatranolazine was slowly released from the SR formulation, and consequentlythe absorption of ranolazine was dissolution-rate limited. This resultedin prolonged plasma drug concentration-time profiles observed at alldose levels, with peak plasma levels at 4 to 6 hours post dose. Over thedose range 500 to 2000 mg, the mean C_(max) and AUC₀ _(⁻) _(30 hr)increased in an approximately dose-proportional manner, although thereappeared to be some deviation proportionality within Group 2.

Example 7

[0121] This Example details a double-blind, placebo-controlled, multipleascending-dose, crossover-designed volunteer study, to evaluate biddosing. Six subjects received 4 days dosing with ranolazine SRformulation prepared according to Example 2D at 500, 750, and 1000 mgbid, followed by a morning dose on Day 5. Pharmacokinetic results arereported in Table 7, below. TABLE 7 Day 5 Ranolazine PharmacokineticParameters (mean ± SD) Ranolazine SR Ranolazine SR Ranolazine SR 500 mgbid 750 mg bid 1000 mg bid Parameter (n = 7) (n = 7) (n = 7) C_(max)(ng/mL) 1760 ± 715  2710 ± 657 3660 ± 1090 T_(max) (hr) 2.00 ± 1.15 4.33 ± 1.62 4.17 ± 2.48 C_(min) (ng/mL) 585 ± 340 1260 ± 501 1960 ±812 

[0122] According to Table 7, ranolazine was slowly released from the SRformulation, and consequently the pharmacokinetics were dissolution-ratelimited. This resulted in extended plasma drug concentration-timeprofiles at all dose levels, with peak plasma levels observed at 2 to 4hours post dose.

[0123] These results indicate that useful ranolazine plasma levels canbe achieved in humans with dosing of this SR formulation on a bidschedule.

Example 8

[0124] This Example evaluated the safety and tolerability ofadministering racemic ranolazine free base formulations as in Example2D. The individual and mean concentrations of racemic ranolazine and itsenantiomers,(R)-(+)-N-(2,6-dimethylphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)-propyl]-1-piperazineacetamide,(S)-(−)-N-(2,6-dimethyphenyl)-4-[2-hydroxy-3-(2-methoxyphenoxy)-propyl]-1-piperazineacetamidein human plasma were also determined.

[0125] The study was performed with ascending doses of sustained releaseranolazine dosage forms. Before and at intervals during and after thedosing period, blood samples were drawn for ranolazine assay and bloodpressure, heart rate, ECG and symptoms were monitored throughout. Datasummaries were reviewed after each phase before proceeding to the nextphase of the study.

[0126] Eight subjects, all healthy male volunteers aged between 18 and40 entered and all completed the study and were available forpharmacokinetic and safety analysis. The subjects were each given dosesof the various types of ranolazine free base in the form of sustainedrelease tablets including 500 mg and 750 mg tablets or with matchingplacebo as necessary (2×750 mg size plus 1×500 mg size) to make unitoral doses of 1500 and 2000 mg.

[0127] In each phase: one dose bid for four days with a single dose onDay 5. On day 5 each volunteer underwent a full pharmacokinetic profileincluding supine and erect blood pressure (BP) and heart rate, ECG data,adverse events, clinical chemistry and hematology results, urinalysisresults.

[0128] Steady state was tested for in each dose level, using C_(48 h),C_(72 h) and C_(96 h) and log transformed data, by analysis ofcovariance and by testing whether the coefficient for time wassignificantly different (defined as p<0.05) from 0. These tests weremade using two-sided t-tests with estimates of variability from theANOVA models. Steady state was also assessed by comparing means forC_(48h), C_(72h) and C_(96h) using a mixed effects ANOVA model anduntransformed and log, transformed data. For hemodynamic parameters, Day1 pre-dose treatment means and Day 5 data were compared acrosstreatments via two-sided t-tests using estimates of variability frommixed effects ANOVA models. Ninety and 95% confidence intervals werecalculated for the treatment comparisons. No adjustments were made formultiple comparisons.

[0129] The mean and standard deviation day 5 pharmacokinetic parametersof ranolazine free base are detailed in Table 8 below and the meanplasma profiles are shown in the figure. Steady-state plasma levels ofranolazine free base appeared to be attained by day 4. Within the doseinterval there was a slow rise to maximum levels with t_(max) valuesranging from 1 to 6 h post-dose. Thereafter levels declined slowly,producing a small degree of fluctuation in plasma levels over the dosinginterval. There appeared to be no differences in the pharmacokineticparameters of the (+) R and (−) S enantiomers of ranolazine followingmultiple dosing with this SR formulation. TABLE 8 Day 5 Racemic (RS),(+)R and (−)S Ranolazine SR Pharmacokinetic Parameters 2000 mg 1500 mgSR bid SR bid (−)S RS ranola- ranola- Parameter RS ranolazine (+)Rranolazine zine zine C_(max) (ng/ml) 5284 ± 2434 2909 ± 1308  2944 ± 7281 ±  1426  2700 C_(min) (ng/ml) 2932 ± 1918 1436 ± 1046  1514 ± 4149 ±  1201  2228 Median t_(max) (h) 4.00 4.00   4.00   4.00 C_(96 h)(ng/ml) 3656 ± 1918 2009 ± 1137  2399 ±  5042 ±  1205  1797 C_(108 h)(ng/ml) 2942 ± 1937 1447 ± 1071  1541 ±  4398 ±  1260  2396AUC_(96-108 h) 49516 ± 23945 25731 ± 13385 26407 ± 68459 ± (ng. h/ml)14849 25842 C_(ave) (ng/ml) 4126 ± 1995 2144 ± 1115  2201 ±  5705 ± 1237  2153 Degree of 0.664 ± 0.336 0.833 ± 0.402  0.824 ±  0.591 ±fluctuation  0.443  0.240

[0130] Some subjects became too symptomatic on standing to complete BPmeasurements on ranolazine 1500 mg (n=3 of 8) and 2000 mg (n=2 of 8),usually 2-6 hours post-dose. Statistically significant reductions inorthostatic systolic BP were noted on day 5 on 1500 mg (−9.8 mm Hg; 4hours post-dose) and 2000 mg (−8.4 mmHg; 6 hours post-dose). Althoughthe pattern of adverse events was similar on ranolazine and placebo,headache, dizziness and blocked nose seemed more common on ranolazine.

What we claim is:
 1. A method for treating a human patient sufferingfrom a cardiovascular disease selected from arrhythmias, variant andexercise-induced angina, and myocardial infarction by administering asustained release pharmaceutical dosage form including at least 50% byweight ranolazine in no more than two tablets per dose to the humanpatient to maintain ranolazine plasma levels in the human patient offrom about 550 to about 7500 ng base/mL for at least 24 hours whereinthe dose is administered at a frequency selected from once, twice andthree times over 24 hours.
 2. The method of claim 1 wherein thesustained release dosage form includes at least one pH dependent binderwherein the pH dependent binder inhibits the release of ranolazine fromthe sustained release dosage form when the sustained release dosage formis subjected to an aqueous environment having a pH of the stomach andwherein the pH dependent binder promotes the release of a therapeuticamount of ranolazine in an aqueous solution having a pH above about 4.5.3. The method of claim 2 wherein the pH dependent binder is partiallyneutralized.
 4. The method of claim 1 wherein the pharmaceutical dosageform is administered to the human patient at a frequency selected fromonce and twice over 24 hours.
 5. The method of claim 1 wherein thepharmaceutical dosage form is administered to the human patient in twodosed over 24 hours wherein each dose consists of two tablets.
 6. Themethod of claim 1 wherein the pharmaceutical dosage form includesbetween about 50% to about 95% by weight ranolazine.
 7. The method ofclaim 1 wherein the pharmaceutical dosage form includes from about 70%to about 80% by weight ranolazine.
 8. The method of claim 2 wherein thepH dependent binder is selected from methacrylic acid copolymers,hydroxypropyl cellulose phthalate, hydroxypropyl methylcellulosephthalate, cellulose acetate phthalate, polyvinyl acetate, phthalate,polyvinylpyrrolidine phthalate, and mixtures thereof.
 9. The method ofclaim 2 wherein the pH dependent binder is a methacrylic acid copolymer.10. The method of claim 9 wherein the methacrylic acid copolymer ismethacrylic acid copolymer Type C USP.
 11. The method of claim 2 whereinthe pH dependent binder is from about 5 to about 12 wt % methacrylicacid copolymer Type C USP.
 12. The method of claim 1 wherein the pHdependent binder is about 10 wt % methacrylic acid copolymer Type C USP.13. The method of claim 1 wherein the pharmaceutical dosage formincludes a pH-independent binder.
 14. The method of claim 13 wherein thepH-independent binder is selected from hydroxypropyl methylcellulose,hydroxypropyl cellulose, poly(meth)acrylate esters,poly-vinylpyrrolidone, and mixtures thereof.
 15. The method of claim 13wherein the pH-independent binder is hydroxypropyl methylcellulose. 16.The method of claim 15 wherein the pharmaceutical dosage form includesfrom about 1 to about 3 wt % hydroxypropyl methylcellulose.
 17. Themethod of claim 15 wherein the pharmaceutical dosage form includes about2 wt % hydroxypropyl methylcellulose.
 18. The method of claim 1 or 6 or7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 wherein thehuman patient plasma ranolazine level ranges from 1000-5000 ng base/mL.19. The method of claim 1 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or14 or 15 or 16 or 17 wherein the human patient plasma ranolazine levelranges from 1000-3800 ng base/mL.
 20. The method of claim 1 or 6 or 7 or8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 wherein the humanpatient plasma ranolazine level ranges from 550-5000 ng base/mL.
 21. Themethod of claim 1 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14 or15 or 16 or 17 wherein the human patient plasma ranolazine level rangesfrom 550-3800 ng base/mL.
 22. The method of claim 1 or 6 or 7 or 8 or 9or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 wherein the humanpatient plasma ranolazine level ranges from 1000-2800 ng base/mL. 23.The method of claim 1 or 6 or 7 or 8 or 9 or 10 or 11 or 12 or 13 or 14or 15 or 16 or 17 wherein the human patient plasma ranolazine levelranges from 1700-3900 ng base/mL.
 24. The method of claim 1 or 6 or 7 or8 or 9 or 10 or 11 or 12 or 13 or 14 or 15 or 16 or 17 wherein the humanpatient plasma ranolazine level ranges from 550-2000 ng base/mL.
 25. Themethod of claim 23 wherein the dosage form includes from 650-850 mgranolazine.
 26. The method of claim 24 wherein the dosage form includesfrom 900-1100 mg ranolazine.
 27. The method of claim 25 wherein thedosage form includes from 400-600 mg ranolazine.
 28. The method of claim22 or 23 or 24 or 25 or 26 or 27 wherein the peak to trough humanpatient plasma ranolazine levels is less than 4:1 over a 24 hour period.29. The method of claim 23 or 24 or 25 or 26 or 27 wherein the peak totrough human patient plasma ranolazine levels is less than 3:1 over a 24hour period.
 30. The method of claim 24 or 28 wherein the peak to troughhuman patient plasma ranolazine levels is less than 2:1 over a 24 hourperiod.
 31. A pharmaceutical dosage form comprising at least about 50 wt% ranolazine and at least one pH dependent binder that inhibits therelease of ranolazine from the sustained release dosage form when thesustained release dosage form is subjected to an aqueous environmenthaving a pH of the stomach and that promotes the release of atherapeutic amount of ranolazine in an aqueous solution having a pHabove about 4.5.
 32. The pharmaceutical dosage form of claim 31including no more than two tablets per dose.
 33. The pharmaceuticaldosage form of claim 32 wherein the pharmaceutical dosage form includesfrom about 50% to about 95% by weight ranolazine.
 34. The pharmaceuticaldosage form of claim 32 wherein the pharmaceutical dosage form includesfrom about 70% to about 80% by weight ranolazine.
 35. The pharmaceuticaldosage form of claim 31 wherein the pH dependent binder is selected frommethacrylic acid copolymers, hydroxypropyl cellulose phthalate,hydroxpropyl methycellulose phthalate, cellulose acetate phthalate,polyvinyl acetate phthalate, polyvinylpyrrolidine phthalate, andmixtures thereof.
 36. The pharmaceutical dosage form of claim 31 whereinthe pH dependent binder is a methacrylic acid copolymer.
 37. Thepharmaceutical dosage form of claim 36 wherein the methacrylic acidcopolymer is methacrylic acid copolymer Type C USP.
 38. Thepharmaceutical dosage form of claim 36 wherein pharmaceutical dosageform includes from about 5 to about 12 wt % methacrylic acid copolymerType C USP.
 39. The pharmaceutical dosage form of claim 36 wherein thepharmaceutical dosage form includes about 10 wt % methacrylic acidcopolymer.
 40. The pharmaceutical dosage form of claim 31 wherein thepharmaceutical dosage form includes a pH-independent binder.
 41. Thepharmaceutical dosage form of claim 40 wherein the pH-independent binderis selected from hydroxypropyl methylcellulose, hydroxypropyl cellulose,poly(meth)acrylate esters, poly-vinylpyrrolidone, and mixtures thereof.42. The pharmaceutical dosage form of claim 40 wherein thepH-independent binder is hydroxypropyl methylcellulose.
 43. Thepharmaceutical dosage form of claim 42 wherein the pharmaceutical dosageform includes from about 1 to about 3 wt % hydroxypropylmethylcellulose.
 44. The pharmaceutical dosage form of claim 42 whereinthe pharmaceutical dosage form includes about 2 wt % hydroxypropylmethylcellulose.
 45. The pharmaceutical dosage form of claim 31 whereinthe dosage form includes from about 650 to about 850 mg ranolazine. 46.The pharmaceutical dosage form of claim 31 wherein the dosage formincludes from about 900 to about 1100 mg ranolazine.
 47. Thepharmaceutical dosage form of claim 31 wherein the dosage form includesfrom about 400 to about 600 mg ranolazine.
 48. The pharmaceutical dosageform of claim 31 wherein the dosage form includes from about 300 toabout 1000 mg ranolazine.
 49. The pharmaceutical dosage form of claim 32wherein the pharmaceutical dosage form is a compressed tablet.
 50. Acompressed tablet comprising from about 70 to about 80 wt % ranolazine,at least one pH dependent binder selected from methacrylic acidcopolymers, hydroxypropyl cellulose phthalate, hydroxypropylmethylcellulose phthalate, cellulose acetate phthalate, polyvinylacetate, phthalate, polyvinylpyrrolidine phthalate, and mixturesthereof, and at least one pH independent binder wherein the compressedtablet includes from about 350 to about 800 mg ranolazine.